Process for the preparation of enantiomeric forms of 2,3-diaminopropionic acid derivatives

ABSTRACT

The disclosure relates to a process for the preparation of the enantiomeric forms of 2,3-diaminopropionic acid derivatives of formula I, 
                         
wherein R1, R2 and R3 are defined as in the disclosure, by racemate resolution. The separation of the racemate into its enantiomers takes place through formation of diastereomeric salts upon addition of an enantiomerically pure auxiliary, and subsequent separation by fractional crystallization.

This application is a continuation of International Application No.PCT/EP2011/063504, filed Aug. 5, 2011, which is incorporated herein byreference in its entirety; which claims the benefit of priority of U.S.Provisional Application No. 61/428,336, filed Dec. 30, 2010, andEuropean Patent Application No. 10305884.8, filed Aug. 12, 2010.

The invention relates to a process for the preparation of theenantiomeric forms of 2,3-diaminopropionic acid derivatives of formula Iby racemate resolution.

The separation of the racemate into its enantiomers takes place throughformation of diastereomeric salts upon addition of an enantiomericallypure auxiliary, and subsequent separation by fractional crystallization.The compounds of formula I are suitable intermediates for thepreparation of IkB kinase inhibitors as described in WO 01/30774 A1, WO2004/022553 A1 and US 2007/0142417 A1, for example.

It is known that enantiomerically pure 2,3-diaminopropionic acidderivatives are used as building blocks for the synthesis of activepharmaceutical ingredients, including IkB kinase inhibitors (cf. WO2004/022553 A1 and US 2007/0142417 A1). Since these building blocks havehitherto only been able to be produced in isolated cases via anasymmetric synthesis, the enantiomerically pure compounds are usuallyobtained via a laborious chromatographic separation of the racemate on achiral stationary phase. These chromatographic methods are very costlyin terms of apparatus time, are limited to small amounts, and useenormous amounts of solvents. Moreover, the chiral stationary phases arevery expensive. This access route to the desired enantiomers thereforeis not very practicable with regard to an industrial production.

It is an object of the present invention to find a technical process forthe preparation of the compounds of formula I which does not have thestated disadvantages.

It has now been found that the separation of the racemate into theenantiomers of formula I through formation of diastereomeric salts uponaddition of an enantiomerically pure auxiliary can also be achieved inthe case of compounds of formula II defined below. The preparation ofthe compound of formula I is thereby effected in a time-saving andcost-saving way with high yields and high enantiomeric purity in amanner which is technically simple to carry out. It also allowsproblem-free scale-up.

The invention therefore relates to a process for obtaining a compound offormula I,

wherein

-   R1 is a hydrogen atom, F, Cl, I, Br, (C₁-C₄)-alkyl or —CN;-   R2 is a heteroaryl residue selected from the series consisting of    pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole,    thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides,    triazolones, oxadiazolone, isoxazolone, oxadiazolidinedione,    triazole, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles,    pyridine, pyrazine, pyrimidine, indole, isoindole, indazole,    phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline,    cinnoline and β-carboline, wherein the heteroaryl residue is    unsubstituted or is substituted once, twice or three times,    independently of each other, by substituents selected from the    series consisting of (C₁-C₅)-alkyl, (C₁-C₅)-alkoxy, halogen, nitro,    amino, trifluoromethyl, hydroxy, hydroxy-(C₁-C₄)-alkyl-,    methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,    hydroxycarbonyl-, aminocarbonyl- and (C₁-C₄)-alkoxycarbonyl-, or an    aryl residue selected from the series consisting of phenyl,    naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl,    3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl, wherein the aryl    residue is unsubstituted or is substituted once, twice or three    times, independently of each other, by substituents selected from    the series consisting of (C₁-C₅)-alkyl, (C₁-C₅)-alkoxy, halogen,    nitro, amino, trifluoromethyl, hydroxy, hydroxy-(C₁-C₄)-alkyl-,    methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,    hydroxycarbonyl-, aminocarbonyl- and (C₁-C₄)-alkoxycarbonyl-;-   R3 is a hydrogen atom,-   or (C₁-C₄)-alkyl,-   or an aryl residue selected from the series consisting of phenyl,    naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl,    3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl, wherein the aryl    residue is unsubstituted or is substituted, independently of each    other, once, twice or three times by substituents selected from the    series consisting of —NO₂, —O—(C₁-C₄)-alkyl, F, Cl and Br,-   or —O—C(CH₃)₃,-   or —O—CH(R7)-aryl, wherein the aryl residue is selected from the    series consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl,    biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and    fluorenyl and is unsubstituted or is substituted, independently of    each other, once, twice or three times by substituents selected from    the series consisting of —NO₂, —O—CH₃, F, Cl and Br, and wherein R7    is a hydrogen atom or (C₁-C₄)-alkyl;

which comprises

-   a) mixing a compound of formula II,

wherein R1, R2 and R3 are defined as in the compound of formula I, in anorganic solvent or a mixture of organic solvents with anenantiomerically pure auxiliary;

-   b) separating the salt composed of enantiomerically pure auxiliary    and compound of formula I, by fractional crystallization; and-   c) isolating the compound of formula I from the salt composed of    enantiomerically pure auxiliary and compound of formula I.

In one embodiment, the invention relates to a process for obtaining acompound of formula I, wherein

-   R1 is a hydrogen atom, F, Cl, I or Br;-   R2 is phenyl, pyridinyl, pyrimidinyl or thiazolyl, wherein phenyl,    pyridinyl, pyrimidinyl and thiazolyl are unsubstituted or    substituted by fluorine or chlorine;-   R3 is phenyl, methyl or —O—C(CH₃)₃;

which comprises

-   a) mixing a compound of formula II, wherein R1, R2 and R3 are    defined as in the compound of formula I, in an organic solvent or a    mixture of organic solvents selected from the series consisting of    n-butyl acetate, ethyl acetate, isopropyl acetate, diisopropyl    ether, methyl tert-butyl ether and diethyl ether, with an    enantiomerically pure auxiliary selected from the series consisting    of (S)-1-phenylethylamine, (R)-1-phenylethylamine,    (S)-1-naphthylethylamine, (R)-1-naphthylethylamine,    (S)-1-cyclohexylethylamine, (R)-1-cyclohexylethylamine,    (S)-1-cyclopropylethylamine and (R)-1-cyclopropylethylamine;-   b) separating the salt composed of enantiomerically pure auxiliary    and compound of formula I, by fractional crystallization; and-   c) isolating the compound of formula I from the salt composed of    enantiomerically pure auxiliary and compound of formula I.

In one embodiment, the group R1 in the compounds and processes accordingto the invention outlined above and below, such as in the compounds offormulae I and II, is a hydrogen atom, F or Cl, in another embodiment itis a hydrogen atom or F, in another embodiment it is a hydrogen atom.

In one embodiment, the group R2 in the compounds and processes accordingto the invention outlined above and below, such as in the compounds offormulae I and II, is a heteroaryl residue selected from the seriesconsisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole,isoxazole, thiazole, isothiazole, tetrazole,1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolone, isoxazolone,oxadiazolidinedione, triazole, 3-hydroxypyrrole-2,4-diones,5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole,isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline,quinazoline, cinnoline and β-carboline, wherein the heteroaryl residueis unsubstituted or is substituted once, twice or three times,independently of each other, by substituents selected from the seriesconsisting of (C₁-C₅)-alkyl, (C₁-C₅)-alkoxy, halogen, nitro, amino,trifluoromethyl, hydroxy, hydroxy-(C₁-C₄)-alkyl-, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl-, aminocarbonyl-and (C₁-C₄)-alkoxycarbonyl-, and in another embodiment is selected fromthe series consisting of pyrrole, furan, thiophene, imidazole, pyrazole,oxazole, isoxazole, thiazole, isothiazole, tetrazole,1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolone, isoxazolone,oxadiazolidinedione, triazole, 3-hydroxypyrrole-2,4-diones,5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole,isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline,quinazoline, cinnoline and β-carboline, wherein the heteroaryl residueis unsubstituted or is substituted once, twice or three times,independently of each other, by substituents selected from the seriesconsisting of (C₁-C₅)-alkyl, (C₁-C₅)-alkoxy and halogen, and in anotherembodiment is unsubstituted or is substituted once, twice or threetimes, independently of each other, by substituents selected from theseries consisting of (C₁-C₅)-alkyl and halogen. In another embodiment R2is phenyl, pyridinyl or pyrimidinyl, in another embodiment it is phenylor pyridinyl, in another embodiment it is pyridinyl, pyrimidinyl orthiazolyl, in another embodiment it is pyridinyl or pyrimidinyl, inanother embodiment it is phenyl, in another embodiment it is pyridinyl,in another embodiment it is pyrimidinyl, in another embodiment it isthiazolyl, wherein phenyl, pyridinyl, pyrimidinyl and thiazolyl areunsubstituted or substituted by fluorine or chlorine, and in anotherembodiment are unsubstituted or substituted by fluorine, and in anotherembodiment are unsubstituted. Pyridinyl representing R2 can be any oneor more of the groups pyridin-2-yl, pyridin-3-yl and pyridin-4-yl,pyrimidinyl representing R2 can be any one or more of the groupspyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl, and thiazolylrepresenting R2 can be any one or of more the groups thiazol-2-yl,thiazol-4-yl and thiazol-5-yl.

In one embodiment, the group R3 in the compounds and processes accordingto the invention outlined above and below, such as in the compounds offormulae I and II, is methyl, —O—C(CH₃)₃ or —O—CH(R7)-aryl, wherein R7is a hydrogen atom and aryl is unsubstituted phenyl, in anotherembodiment it is —O—C(CH₃)₃ or —O—CH(R7)-aryl, wherein R7 is a hydrogenatom and aryl is unsubstituted phenyl, in another embodiment it ismethyl, in another embodiment it is —O—C(CH₃)₃, i.e. a tert-butoxygroup, in another embodiment it is —O—CH(R7)-aryl, wherein R7 is ahydrogen atom and aryl is unsubstituted phenyl, i.e. a benzyloxy group.

The present invention relates to all combinations of definitions ofcompounds and processes with one or more embodiments and/or otherfeatures and/or specific denotations of groups or features specifiedherein.

The terms “(C₁-C₃)-alkyl”, “(C₁-C₄)-alkyl” and “(C₁-C₅)-alkyl” areunderstood as meaning hydrocarbon residues the carbon chain of which isstraight-chain or branched and comprise 1, 2 or 3 carbon atoms, or 1, 2,3 or 4 carbon atoms, or 1, 2, 3, 4 or 5 carbon atoms, respectively.Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl and pentyl.

The term “—CH(R7)-” is understood as meaning straight-chain or branchedhydrocarbon residues such as methylene, ethylene, isopropylene,isobutylene or pentylene. An example of the residue “—CH(R7)-aryl”, inwhich R7 is a hydrogen atom and aryl is phenyl, is the residue benzyl.

If R1 is a hydrogen atom (H), this means that the phenyl residue in thecompounds of formulae I and II and other compounds defined below, whichcarries the group R1, is an unsubstituted phenyl residue. If R1 hasanother meaning than a hydrogen atom, such as F, Cl, I or Br, this meansthat in the phenyl residue carrying R1 a hydrogen atom has been replacedby the respective group or atom, i.e., the said phenyl residue is asubstituted phenyl residue carrying the respective group or atom assubstituent. Such substituents can be present in any position of thephenyl residue, including the 2-position, the 3-position and the4-position. It applies in general to all groups in the compounds offormulae I and II and other compounds defined below, for example toheteroaryl residues and aryl residues representing R2, that substituentscan be present in any suitable position, and that substituents can beidentical or different if more than one substituent is present in agroup.

The term “halogen” is understood as meaning fluorine (F), chlorine (Cl),iodine (I) and bromine (Br). In one embodiment, halogen is F or Cl, inanother embodiment it is F.

The asterisk next to a carbon atom in formula I and the formulae ofother compounds defined below means that the respective compound ispresent as an individual enantiomer, either as R-enantiomer or asS-enantiomer, where the term “present as an individual enantiomer” isunderstood as meaning that the compound is present as a substantiallypure enantiomer with regard to the presence of the opposite enantiomer.In one embodiment, the ee value, i.e. the enantiomeric excess inpercent, of such a substantially pure enantiomer according to theinvention is >90%, in another embodiment >95%, in anotherembodiment >98%, in another embodiment >99%, where the ee value of aspecific sample obtained according to the invention, which is desiredfor the further use of the sample and which is obtainable under theemployed conditions, naturally varies depending on the peculiarities ofthe specific case.

The term “enantiomerically pure auxiliary” is understood as meaningenantiomerically pure amine compounds with at least one center ofchirality which are able to form a diastereomeric salt with thecarboxylic acids of formulae I and II. In one embodiment, such anauxiliary with one center of chirality is employed. In anotherembodiment, such an auxiliary is a compound from the substance classesof chiral 1-aryl-ethylamines, 1-cycloalkyl-ethylamines,1-aryl-propylamines and 1-cycloalkyl-propylamines, wherein aryl is, forexample, phenyl or naphthyl including 1-naphthyl and 2-naphthyl, and isunsubstituted or substituted once, twice or three times, independentlyof each other, by substituents selected from the series consisting of(C₁-C₅)-alkyl, (C₁-C₅)-alkoxy and halogen, and cycloalkyl is, forexample, cyclopropyl or cyclohexyl. In one embodiment, theenantiomerically pure auxiliary is selected from the series consistingof (S)-1-phenylethylamine, (R)-1-phenylethylamine,(S)-1-phenylpropylamine, (R)-1-phenylpropylamine,(S)-1-naphthylethylamine, (R)-1-naphthylethylamine,(S)-1-cyclohexylethylamine, (R)-1-cyclohexylethylamine,(S)-1-cyclopropylethylamine and (R)-1-cyclopropylethylamine, in anotherembodiment from the series consisting of (S)-1-phenylethylamine and(R)-1-phenylethylamine, and in another embodiment it is(S)-1-phenylethylamine. The chemical purity of the employedenantiomerically pure auxiliary should be >95% and the enantiomericexcess >90%. The chirality of the auxiliary to be employed in a specificcase depends on the peculiarities of the case and the desired chiralityof the compound of formula I.

The term “fractional crystallization” is understood as meaning aseparation method which utilizes differences in the solubility of thesubstances in order to separate crystals. The crystallization can becaused by concentration changes, changes in the temperature or othertriggers such as the Use of seed crystals, for example.

For the fractional crystallization method, the racemic compound offormula II can be suspended or dissolved in a suitable solvent orsolvent mixture. Suitable solvents are, for example, esters such asn-butyl acetate, ethyl acetate or isopropyl acetate, and ethers such asdiisopropyl ether, methyl tert-butyl ether or diethyl ether. In oneembodiment, solvents selected from the series consisting of n-butylacetate, ethyl acetate, isopropyl acetate, diisopropyl ether and methyltert-butyl ether, in another embodiment from the series consisting ofn-butyl acetate and diisopropyl ether, or mixtures thereof, areemployed. An enantiomerically pure auxiliary is then added to thissolution or sUspension with stirring, for example(S)-1-phenylethylamine, (R)-1-phenylethylamine,(S)-1-naphthylethylamine, (R)-1-naphthylethylamine,(S)-1-cyclohexylethylamine, (R)-1-cyclohexylethylamine,(S)-1-cyclopropylethylamine, (R)-1-cyclopropylethylamine, in particular(S)-1-phenylethylamine or (R)-1-phenylethylamine. The order in which thecompound of formula II and the enantiomerically pure auxiliary areintroduced, can also be inverted. The molar ratio of the compound offormula II to the enantiomerically pure auxiliary is advantageoUsly fromabout 0.5 to about 1.1. In one embodiment, the molar ratio of thecompound of formula II to the enantiomerically pure auxiliary is fromabout 0.9 to about 1.1, in another embodiment from about 0.9 to about1.0, in another embodiment from about 1.0 to about 1.1.

The mixing operation of the compound of formula II with theenantiomerically pure auxiliary is Usually carried out at temperaturesfrom about 20° C. up to the boiling point of the employed solvent orsolvent mixture, preferably at elevated temperatures up to the boilingpoint, for example at temperatures from about 20° C. to about 60° C., orat temperatures from about 40° C. to about 60° C., or at temperaturesfrom about 40° C. up to the boiling point. The mixing Usually takesplace over a certain time period, for example over a period of fromabout 1 hour to about 5 hours. In order to ensure a complete reaction ofthe compound of formula II with the auxiliary, the mixture is Usuallyheld at temperature for some time.

The fractional crystallization can be initiated by cooling a heatedmixture comprising the compound of formula II and the enantiomericallypure auxiliary, and/or partial evaporation of the solvent, and/or addinga further solvent, and/or adding seed crystals. The cooling is favorablyperformed slowly until crystals comprising the salt composed of thecompound of formula I and the enantiomerically pure auxiliaryprecipitate. For completion of the crystallization, the mixture isUsually cooled to end temperatures of about 0° C. to about 30° C., inparticular to temperatures of about 5° C. to about 20° C. The crystalscomprising the salt composed of the compound of formula I and theenantiomerically pure auxiliary are separated and washed with a suitablesolvent. The separation can take place by filtration or centrifugation,for example. Suitable solvents are, for example, esters such as n-butylacetate, ethyl acetate or isopropyl acetate, or ethers such asdiisopropyl ether or methyl tert-butyl ether. If desired, the resultingcrystals can be dried, for example at elevated temperatures such as atabout 60° C., under reduced pressure or at atmospheric pressure.

The remaining mother liquor, from which the crystals comprising the saltcomposed of the compound of formula I and the enantiomerically pureauxiliary have been separated, comprises the salt, remaining insolution, composed of the undesired opposite enantiomer of the compoundof formula I and the enantiomerically pure auxiliary. After work-up andseparation of the compound of formula I from the enantiomerically pureauxiliary, the undesired enantiomer can optionally be racemized, forexample via base-induced racemization of an anhydride or active esterformed in situ, and subjected to a further racemate resolution inaccordance with the aforementioned process, i.e., the undesiredenantiomer can be recycled.

The isolation of the desired compound of formula I from the separatedcrystals, in which it is present in the form of the salt with theenantiomerically pure auxiliary, can be performed according to methodsknown to the person skilled in the art. For example, the crystalscomprising the salt composed of the compound of formula I and theenantiomerically pure auxiliary can be suspended or dissolved in asuitable solvent, and the suspension or solution admixed with a suitableacid, for example sulfuric acid, for example at temperatures from about10° C. to about 30° C. such as at room temperature. The auxiliary thendissolves, or remains in solution, and the compound of formula Igenerally precipitates and can be separated in the form of a solid, orotherwise can be obtained by standard procedures. Suitable solvents are,for example, alcohols such as methanol, ethanol and isopropanol, oresters such as ethyl acetate, isopropyl acetate and n-butyl acetate, ormixtures of solvents including mixtures of alcohols with water. Theexplanations given above with respect to the procedures for obtainingthe salt composed of the compound of formula I and the enantiomericallypure auxiliary apply correspondingly to the procedures for obtaining thecompound of formula I.

The invention also relates to a process for obtaining a compound offormula IV or a salt thereof,

wherein

-   R1, R2 and R3 are defined as in the compound of formula I;-   R5 is —NH₂, —N(H)—R6 or —N(R6)₂, wherein R6 is (C₁-C₄)-alkyl or    aryl, wherein the aryl residue is selected from the series    consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl,    2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl;

which comprises

-   a) mixing a compound of formula II, wherein R1, R2 and R3 are    defined as in the compound of formula I, in an organic solvent or a    mixture of organic solvents with an enantiomerically pure auxiliary;-   b) separating the salt composed of enantiomerically pure auxiliary    and compound of formula I, by fractional crystallization;-   c) isolating the compound of formula I from the salt composed of    enantiomerically pure auxiliary and compound of formula I; and-   d) converting the resulting compound of formula I with ammonia or an    amine of the formula H₂N—R6 or HN(R6)₂, wherein R6 is (C₁-C₄)-alkyl    or aryl, wherein the aryl residue is selected from the series    consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl,    2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl,    into the compound of formula IV or a salt thereof.

In one embodiment, the invention relates to a process for obtaining acompound of formula IV or a salt thereof, wherein

-   R1 is a hydrogen atom, F, Cl, I or Br;-   R2 is phenyl, pyridinyl, pyrimidinyl or thiazolyl, wherein phenyl,    pyridinyl, pyrimidinyl and thiazolyl are unsubstituted or    substituted by fluorine or chlorine;-   R3 is phenyl, methyl or —O—C(CH₃)₃;-   R5 is —NH₂, —N(H)—R6 or —N(R6)₂, wherein R6 is (C₁-C₄)-alkyl or    aryl, wherein the aryl residue is selected from the series    consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl,    2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl;

which comprises

-   a) mixing a compound of formula II, wherein R1, R2 and R3 are    defined as in the compound of formula I, in an organic solvent or a    mixture of organic solvents selected from the series consisting of    n-butyl acetate, ethyl acetate, isopropyl acetate, diisopropyl    ether, methyl tert-butyl ether and diethyl ether, with an    enantiomerically pure auxiliary selected from the series consisting    of (S)-1-phenylethylamine, (R)-1-phenylethylamine,    (S)-1-naphthylethylamine, (R)-1-naphthylethylamine,    (S)-1-cyclohexylethylamine, (R)-1-cyclohexylethylamine,    (S)-1-cyclopropylethylamine and (R)-1-cyclopropylethylamine;-   b) separating the salt composed of enantiomerically pure auxiliary    and compound of formula I, by fractional crystallization;-   c) isolating the compound of formula I from the salt composed of    enantiomerically pure auxiliary and compound of formula I; and-   d) converting the resulting compound of formula I with ammonia or an    amine of the formula H₂N—R6 or HN(R6)₂, wherein R6 is (C₁-C₄)-alkyl    or aryl, wherein the aryl residue is selected from the series    consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl,    2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl,    into the compound of formula IV or a salt thereof.

In one embodiment, the group R5 in the compounds and processes accordingto the invention outlined above and below, such as the compounds offormula IV, is —NH₂ or —N(H)—R6, in another embodiment it is —NH₂.

In one embodiment, the group R6 in the compounds and processes accordingto the invention outlined above and below, such as the compounds offormula IV, is (C₁-C₄)-alkyl, in another embodiment it is methyl.

The explanations given above, such as with respect to the groups R1, R2and R3 or process steps a), b) and c), apply correspondingly to thecompounds of formula IV and the process for their preparation definedafore. Process step d) can be carried out, for example, according tomethods, and under reaction conditions, for the formation ofcarboxamides from carboxylic acids which are known to the person skilledin the art and are described, for example, in M. B. Smith and J. March,March's Advanced Organic Chemistry, 5th edition, Wiley-Interscience, NewYork, 2001. In general, for the formation of a carboxamide thecarboxylic acid is activated with a suitable reagent, such as1,1′-carbonyldiimidazole or a carbodiimide likeN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, in aninert solvent such as an ether like tetrahydrofuran or acetonitrile attemperatures from about −20° C. up to boiling point of the solvent, andconverted into the respective amide of formula IV by adding ammonia orthe desired amine.

The invention also relates to a process for obtaining a compound offormula III or a salt thereof,

wherein R1 and R2 are defined as in the compound of formula I;

-   R5 is —NH₂, —N(H)—R6 or —N(R6)₂, wherein R6 is (C₁-C₄)-alkyl or    aryl, wherein the aryl residue is selected from the series    consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl,    2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl;

which comprises

-   a) mixing a compound of formula II, wherein R1, R2 and R3 are    defined as in the compound of formula I, in an organic solvent or a    mixture of organic solvents with an enantiomerically pure auxiliary;-   b) separating the salt composed of enantiomerically pure auxiliary    and compound of formula I, by fractional crystallization;-   c) isolating the compound of formula I from the salt composed of    enantiomerically pure auxiliary and compound of formula I;-   d) converting the resulting compound of formula I with ammonia or an    amine of the formula H₂N—R6 or HN(R6)₂, wherein R6 is (C₁-C₄)-alkyl    or aryl, wherein the aryl residue is selected from the series    consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl,    2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl,    into a compound of formula IV or a salt thereof; and-   e) converting the resulting compound of formula IV or salt thereof    into the compound of formula III or a salt thereof.

In one embodiment, the invention relates to a process for obtaining acompound of formula III or a salt thereof, wherein

-   R1 is a hydrogen atom, F, Cl, I or Br;-   R2 is phenyl, pyridinyl, pyrimidinyl or thiazolyl, wherein phenyl,    pyridinyl, pyrimidinyl and thiazolyl are unsubstituted or    substituted by fluorine or chlorine;-   R5 is —NH₂, —N(H)—R6 or —N(R6)₂, wherein R6 is (C₁-C₄)-alkyl or    aryl, wherein the aryl residue is selected from the series    consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl,    2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl;

which comprises

-   a) mixing a compound of formula II, wherein R1, R2 and R3 are    defined as in the compound of formula I, in an organic solvent or a    mixture of organic solvents selected from the series consisting of    n-butyl acetate, ethyl acetate, isopropyl acetate, diisopropyl    ether, methyl tert-butyl ether and diethyl ether, with an    enantiomerically pure auxiliary selected from the series consisting    of (S)-1-phenylethylamine, (R)-1-phenylethylamine,    (S)-1-naphthylethylamine, (R)-1-naphthylethylamine,    (S)-1-cyclohexylethylamine, (R)-1-cyclohexylethylamine,    (S)-1-cyclopropylethylamine and (R)-1-cyclopropylethylamine;-   b) separating the salt composed of enantiomerically pure auxiliary    and compound of formula I, by fractional crystallization;-   c) isolating the compound of formula I from the salt composed of    enantiomerically pure auxiliary and compound of formula I;-   d) converting the resulting compound of formula I with ammonia or an    amine of the formula H₂N—R6 or HN(R6)₂, wherein R6 is (C₁-C₄)-alkyl    or aryl, wherein the aryl residue is selected from the series    consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl,    2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl,    into a compound of formula IV or a salt thereof; and-   e) converting the resulting compound of formula IV or a salt thereof    into the compound of formula III or a salt thereof.

The explanations given above, such as with respect to the groups R1, R2,R3 and R5 or process steps a), b), c) and d), apply correspondingly tothe compounds of formula III and the process for their preparationdefined afore. Process step e) can be carried out, for example,according to methods, and under reaction conditions, for the cleavage ofcarboxamides and carbamates to give the amines which are known to theperson skilled in the art and are described, for example, in M. B. Smithand J. March, March's Advanced Organic Chemistry, 5th edition,Wiley-Interscience, New York, 2001; or in D. L. Flynn et al., J. Org.Chem. 1983, 48, 2424; or in M. J. Burk et al., J. Org. Chem. 1997, 62,7054. For example, the cleavage of a tert-butoxycarbonyl grouprepresenting the group R3-C(O)— in the compounds of formula IV to givecompounds of formula III can be performed under standard conditions suchas treatment with trifluoroacetic acid (TFA), hydrochloric acid orp-toluenesulfonic acid in a suitable solvent, such as a chlorinatedhydrocarbon like dichloromethane or water, at temperatures from about 0°C. to about 50° C.

The preparation of salts of compounds of formulae III and IV capable ofsalt formation, including their stereoisomeric forms, in process step d)and e), respectively, can be performed according to standard proceduresknown per se. If the compounds of formulae III and IV contain acidgroups, stable alkali metal salts, alkaline earth metal salts andoptionally substituted ammonium salts and amidinium salts can beprepared Using basic reagents such as hydroxides, carbonates,hydrogencarbonates, alcoholates, ammonia or organic bases, for exampleamines like trimethylamine, triethylamine, ethanolamine, diethanolamine,triethanolamine, trometamol, amidines like1,8-diazabicyclo[5.4.0]undec-7-ene, or basic amino acids like lysine,ornithine or arginine. If the compounds of formulae III and IV containbasic groups, stable acid addition salts can be prepared Using acidicreagents including inorganic acids and organic acids like hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid,4-bromobenzenesulfonic acid, cyclohexylamidosulfonic acid,trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, aceticacid, oxalic acid, tartaric acid, succinic acid, glycerolphosphoricacid, lactic acid, malic acid, adipic acid, citric acid, fumaric acid,maleic acid, gluconic acid, glucuronic acid, palmitic acid ortrifluoroacetic acid. These explanations apply likewise to salts ofother compounds according to the invention, such as compounds offormulae I, II or IIb, which are capable of salt formation, and whichcan be employed in the processes of the invention, or obtained by them,or are a subject of the invention, just so in the form of their salts.

Under these conditions, enantiomeric purities of >99% ee are achieved inthe preparation of compounds of formulae I, III and IV according to theprocesses of the invention without the need for repeated additionalenrichment steps such as recrystallizations.

The starting compounds of formula II are known or can be preparedaccording to, or analogously to, procedures described in the literature.For example, compounds of formula VI, which can be synthesizedanalogously as described in K. El Abdioui et al., Bull. Soc. Chim. Belg.1997, 106, 425 or P. M. T. Ferreira et al., J. Chem. Soc., Perkin Trans.1, 1999, 3697, can be reacted with amines of formula V in a suitablesolvent, such as an ether like tetrahydrofuran or diisopropyl ether,favorably in the presence of a base such as an alkali metal alkoxidelike lithium tert-butoxide or an alkali metal carbonate like cesiumcarbonate at temperatures from about −10° C. to about 30° C., to givecompounds of formula IIa.

The resulting compound of formula IIa can be converted into a compoundof formula IIb, in which R4 is a hydrogen atom or an alkali metal ionsuch as lithium, sodium, potassium, rubidium or cesium, i.e. the groupR4-O—C(O)— is a carboxylic acid group or an alkali metal salt thereof,by treatment with an alkali metal hydroxide such as lithium hydroxide(LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), rubidiumhydroxide (RbOH) or cesium hydroxide (CsOH), for example sodiumhydroxide, in a suitable solvent or a mixture of solvents, such as wateror an ether like tetrahydrofuran or dioxane or a mixture of water and anether, at temperatures from about 0° C. to about 120° C., for exampletemperatures from about 20° C. to about 80° C., or temperatures fromabout 20° C. to about 60° C. The reaction time generally is from about0.5 hours to about 8 hours, depending on the composition of the reactionmixture and the selected temperature range. The resulting compound offormula IIb is then isolated from the reaction mixture by standardprocedures, as applies to the isolation of all compounds preparedaccording to the present invention, for example by aqueous work-up,optionally with addition of an acid such as sulfuric acid, andextraction with a suitable solvent, for example ethyl acetate ordichloromethane, or crystallization.

In the compounds of formulae VI, V, IIa and IIb,

-   R1, R2 and R3 are defined as in the compounds of formula I;-   R4 is a hydrogen atom or an alkali metal ion;-   R9 is (C₁-C₄)-alkyl or —CH(R8)-aryl, wherein the aryl residue is    selected from the series consisting of phenyl, naphthyl, 1-naphthyl,    2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,    anthryl and fluorenyl, and wherein R8 is a hydrogen atom or    (C₁-C₄)-alkyl;-   R10 and R11 are, independently of one another,-   a hydrogen atom,-   or (C₁-C₄)-alkyl,-   or an aryl residue selected from the series consisting of phenyl,    naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl,    3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl, wherein the aryl    residue is unsubstituted or is substituted, independently of each    other, once, twice or three times by substituents selected from the    series consisting of —NO₂, —O—(C₁-C₄)-alkyl, F, Cl and Br,-   or —O—C(CH₃)₃,-   or —O—CH(R7)-aryl, wherein the aryl residue is selected from the    series consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl,    biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and    fluorenyl and is unsubstituted or is substituted, independently of    each other, once, twice or three times by substituents selected from    the series consisting of —NO₂, —O—CH₃, F, Cl and Br, and wherein R7    is a hydrogen atom or (C₁-C₄)-alkyl.

The simultaneous cleavage of two different protective groups, i.e. oneof the acyl groups R3-C(O)— and R10-C(O)— at the nitrogen atom and theester function R9-O—C(O)— protecting the carboxylic acid group, in theconversion of the compounds of formula IIa into the compounds of formulaIIb surprisingly proceeds in a selective manner and without by-productformation, and thus produces compounds of formula IIb in high yields.This novel, highly selective one-pot reaction is thus optimally suitedfor industrial production.

The invention thus also relates to a process for obtaining a compound offormula IIb,

wherein

-   R1 and R2 are defined as in the compound of formula I;-   R4 is a hydrogen atom or an alkali metal ion;-   R11 is a hydrogen atom,-   or (C₁-C₄)-alkyl,-   or an aryl residue selected from the series consisting of phenyl,    naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl,    3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl, wherein the aryl    residue is unsubstituted or is substituted, independently of each    other, once, twice or three times by substituents selected from the    series consisting of —NO₂, —O—(C₁-C₄)-alkyl, F, Cl and Br,-   or —O—C(CH₃)₃,-   or —O—CH(R7)-aryl, wherein the aryl residue is selected from the    series consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl,    biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and    fluorenyl and is unsubstituted or is substituted, independently of    each other, once, twice or three times by substituents selected from    the series consisting of —NO₂, —O—CH₃, F, Cl and Br, and wherein R7    is a hydrogen atom or (C₁-C₄)-alkyl;

which comprises reacting a compound of formula IIa,

wherein

-   R1, R2 and R3 are defined as in the compound of formula I;-   R9 is (C₁-C₄)-alkyl or —CH(R8)-aryl, wherein the aryl residue is    selected from the series consisting of phenyl, naphthyl, 1-naphthyl,    2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,    anthryl and fluorenyl, and wherein R8 is a hydrogen atom or    (C₁-C₄)-alkyl;-   R10 is a hydrogen atom,-   or (C₁-C₄)-alkyl,-   or an aryl residue selected from the series consisting of phenyl,    naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl,    3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl, wherein the aryl    residue is unsubstituted or is substituted, independently of each    other, once, twice or three times by substituents selected from the    series consisting of —NO₂, —O—(C₁-C₄)-alkyl, F, Cl and Br,-   or —O—C(CH₃)₃,-   or —O—CH(R7)-aryl, wherein the aryl residue is selected from the    series consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl,    biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and    fluorenyl and is unsubstituted or is substituted, independently of    each other, once, twice or three times by substituents selected from    the series consisting of —NO₂, —O—CH₃, F, Cl and Br, and wherein R7    is a hydrogen atom or (C₁-C₄)-alkyl;-   with an alkali metal hydroxide to give a compound of formula IIb.

The explanations given above, such as with respect to the groups R1, R2and R3, apply correspondingly to the compounds of formulae IIb and IIaand the process for their conversion. Explanations relating specificallyto the conversion of the compounds of formula IIa into compounds offormula IIb are already given afore.

In one embodiment, the invention relates to a process for obtaining acompound of formula IIb, wherein

-   R1 is a hydrogen atom, F, Cl, I or Br;-   R2 is phenyl, pyridinyl, pyrimidinyl or thiazolyl, wherein phenyl,    pyridinyl, pyrimidinyl and thiazolyl are unsubstituted or    substituted by fluorine or chlorine;-   R4 is a hydrogen atom;-   R11 is phenyl, methyl or —O—C(CH₃)₃;

which comprises reacting a compound of formula IIa, wherein

-   R1 and R2 are defined as in the compound of formula IIb;-   R3 and R10 are, independently of one another, phenyl, methyl or    —O—C(CH₃)₃;-   R9 is methyl or ethyl;-   with an alkali metal hydroxide to give a compound of formula IIb.

In one embodiment, the group R4 in the compounds and processes accordingto the invention outlined above and below, such as the compounds offormula IIb, is a hydrogen atom or a sodium ion, in another embodimentit is a hydrogen atom.

In one embodiment, the group R9 in the compounds and processes accordingto the invention outlined above and below, such as the compounds offormula IIa, is (C₁-C₄)-alkyl, in another embodiment it is(C₁-C₃)-alkyl, in another embodiment it is methyl or ethyl, in anotherembodiment it is methyl.

In one embodiment, the group R10 in the compounds and processesaccording to the invention outlined above and below, such as thecompounds of formula IIa, is methyl, —O—C(CH₃)₃ or —O—CH(R7)-aryl,wherein R7 is a hydrogen atom and aryl is unsubstituted phenyl, inanother embodiment it is —O—C(CH₃)₃ or —O—CH(R7)-aryl, wherein R7 is ahydrogen atom and aryl is unsubstituted phenyl, in another embodiment itis methyl, in another embodiment it is —O—C(CH₃)₃, in another embodimentit is —O—CH(R7)-aryl, wherein R7 is a hydrogen atom and aryl isunsubstituted phenyl.

In one embodiment, the group R11 in the compounds and processesaccording to the invention outlined above and below, such as thecompounds of formula IIb, is methyl, —O—C(CH₃)₃ or —O—CH(R7)-aryl,wherein R7 is a hydrogen atom and aryl is unsubstituted phenyl, inanother embodiment it is —O—C(CH₃)₃ or —O—CH(R7)-aryl, wherein R7 is ahydrogen atom and aryl is unsubstituted phenyl, in another embodiment itis methyl, in another embodiment it is —O—C(CH₃)₃, in another embodimentit is —O—CH(R7)-aryl, wherein R7 is a hydrogen atom and aryl isunsubstituted phenyl.

A further aspect of the present invention are the 2,3-diaminopropionicacid derivatives, or 2,3-diaminopropanoic acid derivatives, of formulaeI, III and IV per se, also in the form of a mixture of the enantiomers,and in the form of their salts, which are likewise provided by theinvention. The term “mixture of enantiomers” is to be understood here inparticular as meaning a mixture of enantiomers in which one enantiomeris enriched compared to its opposite enantiomer, or is present insubstantially pure form and, for example, the enantiomeric excess eeis >90% in one embodiment, or >95% in another embodiment, or >98% inanother embodiment, or >99% in another embodiment.

Thus, the invention also relates to novel compounds of formula I,

wherein

-   R1 is a hydrogen atom, F, Cl, I, Br, (C₁-C₄)-alkyl or —CN;-   R2 is a heteroaryl residue selected from the series consisting of    pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole,    thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole 2-oxides,    triazolones, oxadiazolone, isoxazolone, oxadiazolidinedione,    triazole, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles,    pyridine, pyrazine, pyrimidine, indole, isoindole, indazole,    phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline,    cinnoline and β-carboline, wherein the heteroaryl residue is    unsubstituted or is substituted once, twice or three times,    independently of each other, by substituents selected from the    series consisting of (C₁-C₅)-alkyl, (C₁-C₅)-alkoxy, halogen, nitro,    amino, trifluoromethyl, hydroxy, hydroxy-(C₁-C₄)-alkyl-,    methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,    hydroxycarbonyl-, aminocarbonyl- and (C₁-C₄)-alkoxycarbonyl-,-   or an aryl residue selected from the series consisting of phenyl,    naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl,    3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl, wherein the aryl    residue is unsubstituted or is substituted once, twice or three    times, independently of each other, by substituents selected from    the series consisting of (C₁-C₅)-alkyl, (C₁-C₅)-alkoxy, halogen,    nitro, amino, trifluoromethyl, hydroxy, hydroxy-(C₁-C₄)-alkyl-,    methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,    hydroxycarbonyl-, aminocarbonyl- and (C₁-C₄)-alkoxycarbonyl-;-   R3 is a hydrogen atom,-   or (C₁-C₄)-alkyl,-   or an aryl residue selected from the series consisting of phenyl,    naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl,    3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl, wherein the aryl    residue is unsubstituted or is substituted, independently of each    other, once, twice or three times by substituents selected from the    series consisting of —NO₂, —O—(C₁-C₄)-alkyl, F, Cl and Br,-   or —O—C(CH₃)₃,-   or —O—CH(R7)-aryl, wherein the aryl residue is selected from the    series consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl,    biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and    fluorenyl and is unsubstituted or is substituted, independently of    each other, once, twice or three times by substituents selected from    the series consisting of —NO₂, —O—CH₃, F, Cl and Br, and wherein R7    is a hydrogen atom or (C₁-C₄)-alkyl;-   provided that the compound of formula I is not    (S)-2-benzyloxycarbonylamino-3-diphenylamino-propionic acid, i.e.    the compound of formula I wherein R1 is a hydrogen atom, R2 is    unsubstituted phenyl, R3 is —CH(R7)-aryl wherein aryl is    unsubstituted phenyl and R7 is a hydrogen atom, and the chiral    carbon atom has S configuration.

In one embodiment, the invention relates to novel compounds of formulaI, wherein

-   R1 is a hydrogen atom, F, Cl, I or Br;-   R2 is phenyl, pyridinyl, pyrimidinyl or thiazolyl, wherein phenyl,    pyridinyl, pyrimidinyl and thiazolyl are unsubstituted or    substituted by fluorine or chlorine;-   R3 is phenyl, methyl or —O—C(CH₃)₃.

Another aspect of the invention relates to novel compounds of formulaII, which are the starting compounds for the preparation of thecompounds of formula I according to the invention,

wherein

-   R1 is a hydrogen atom, F, Cl, I, Br, (C₁-C₄)-alkyl or —CN;-   R2 is a heteroaryl residue selected from the series consisting of    pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole,    thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole 2-oxides,    triazolones, oxadiazolone, isoxazolone, oxadiazolidinedione,    triazole, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles,    pyridine, pyrazine, pyrimidine, indole, isoindole, indazole,    phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline,    cinnoline and β-carboline, wherein the heteroaryl residue is    unsubstituted or is substituted once, twice or three times,    independently of each other, by substituents selected from the    series consisting of (C₁-C₅)-alkyl, (C₁-C₅)-alkoxy, halogen, nitro,    amino, trifluoromethyl, hydroxy, hydroxy-(C₁-C₄)-alkyl-,    methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,    hydroxycarbonyl-, aminocarbonyl- and (C₁-C₄)-alkoxycarbonyl-,-   or an aryl residue selected from the series consisting of phenyl,    naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl,    3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl, wherein the aryl    residue is unsubstituted or is substituted once, twice or three    times, independently of each other, by substituents selected from    the series consisting of (C₁-C₅)-alkyl, (C₁-C₅)-alkoxy, halogen,    nitro, amino, trifluoromethyl, hydroxy, hydroxy-(C₁-C₄)-alkyl-,    methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,    hydroxycarbonyl-, aminocarbonyl- and (C₁-C₄)-alkoxycarbonyl-;-   R3 is a hydrogen atom,-   or (C₁-C₄)-alkyl,-   or an aryl residue selected from the series consisting of phenyl,    naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl,    3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl, wherein the aryl    residue is unsubstituted or is substituted, independently of each    other, once, twice or three times by substituents selected from the    series consisting of —NO₂, —O—(C₁-C₄)-alkyl, F, Cl and Br,-   or —O—C(CH₃)₃,-   or —O—CH(R7)-aryl, wherein the aryl residue is selected from the    series consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl,    biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and    fluorenyl and is unsubstituted or is substituted, independently of    each other, once, twice or three times by substituents selected from    the series consisting of —NO₂, —O—CH₃, F, Cl and Br, and wherein R7    is a hydrogen atom or (C₁-C₄)-alkyl.

In one embodiment, the invention relates to novel compounds of formulaII, wherein

-   R1 is a hydrogen atom, F, Cl, I or Br;-   R2 is phenyl, pyridinyl, pyrimidinyl or thiazolyl, wherein phenyl,    pyridinyl, pyrimidinyl and thiazolyl are unsubstituted or    substituted by fluorine or chlorine;-   R3 is phenyl, methyl or —O—C(CH₃)₃.

The invention further relates to compounds of formula III selected fromthe series consisting of(S)-2-amino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide (formulaIIIa), or a salt thereof, and(R)-2-amino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide (formulaIIb), or a salt thereof. In one embodiment, the compound of formula IIIis the compound of formula IIIa, or a salt thereof, and in anotherembodiment it is the compound of formula IIIb, or a salt thereof.

The invention further relates to novel compounds of formula IV,

wherein

-   R1 is a hydrogen atom, F, Cl, I, Br, (C₁-C₄)-alkyl or —CN,-   R2 is a heteroaryl residue selected from the series consisting of    pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole,    thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole 2-oxides,    triazolones, oxadiazolone, isoxazolone, oxadiazolidinedione,    triazole, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles,    pyridine, pyrazine, pyrimidine, indole, isoindole, indazole,    phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline,    cinnoline and β-carboline, wherein the heteroaryl residue is    unsubstituted or is substituted once, twice or three times,    independently of each other, by substituents selected from the    series consisting of (C₁-C₅)-alkyl, (C₁-C₅)-alkoxy, halogen, nitro,    amino, trifluoromethyl, hydroxy, hydroxy-(C₁-C₄)-alkyl-,    methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,    hydroxycarbonyl-, aminocarbonyl- and (C₁-C₄)-alkoxycarbonyl-,-   or an aryl residue selected from the series consisting of phenyl,    naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl,    3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl, wherein the aryl    residue is unsubstituted or is substituted once, twice or three    times, independently of each other, by substituents selected from    the series consisting of (C₁-C₅)-alkyl, (C₁-C₅)-alkoxy, halogen,    nitro, amino, trifluoromethyl, hydroxy, hydroxy-(C₁-C₄)-alkyl-,    methylenedioxy, ethylenedioxy, formyl, acetyl, cyano,    hydroxycarbonyl-, aminocarbonyl- and (C₁-C₄)-alkoxycarbonyl-;-   R3 is a hydrogen atom,-   or (C₁-C₄)-alkyl,-   or an aryl residue selected from the series consisting of phenyl,    naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl,    3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl, wherein the aryl    residue is unsubstituted or is substituted, independently of each    other, once, twice or three times by substituents selected from the    series consisting of —NO₂, —O—(C₁-C₄)-alkyl, F, Cl and Br,-   or —O—C(CH₃)₃,-   or —O—CH(R7)-aryl, wherein the aryl residue is selected from the    series consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl,    biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and    fluorenyl and is unsubstituted or is substituted, independently of    each other, once, twice or three times by substituents selected from    the series consisting of —NO₂, —O—CH₃, F, Cl and Br, and wherein R7    is a hydrogen atom or (C₁-C₄)-alkyl;-   R5 is —NH₂, —N(H)—R6 or —N(R6)₂, wherein R6 is (C₁-C₄)-alkyl or    aryl, wherein the aryl residue is selected from the series    consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl,    2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl.

In one embodiment, the invention relates to novel compounds of formulaIV, wherein

-   R1 is a hydrogen atom, F, Cl, I or Br;-   R2 is phenyl, pyridinyl, pyrimidinyl or thiazolyl, wherein phenyl,    pyridinyl, pyrimidinyl and thiazolyl are unsubstituted or    substituted by fluorine or chlorine;-   R3 is phenyl, methyl or —O—C(CH₃)₃;-   R5 is —NH₂.

As already indicated, the explanations given above and the embodimentsdefined above, such as with respect to the groups R1, R2, R3 and R5apply correspondingly to the compounds of formulae I, II, III and IVwhich are a subject of the invention as compounds per se. The compoundsof formulae I, II, III and IV are suitable as intermediate compounds forthe preparation of IkB kinase inhibitors as described in WO 01/30774 A1,WO 2004/022553 A1 and US 2007/0142417 A1, for example.

The invention is illustrated below in more detail by reference toexamples. End products are generally characterized by ¹H-NMR (400 MHz,in DMSO-d₆, unless indicated otherwise), mass spectrometry andoptionally chiral HPLC analysis. Temperature data are given in degreeCelsius. RT means room temperature (about 22° C. to 26° C.). Anyabbreviations Used are either explained or correspond to standardconventions.

EXAMPLE 1 Preparation of2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid

Step 1

A solution of 2-anilino-pyrimidine (71 g, 415 mmol; prepared inaccordance with T. Matsukawa et al., Yakugaku Zasshi 1951, 71, 933) andlithium tert-butoxide (14 g, 175 mmol) in tetrahydrofuran (170 ml) iscooled to −5° C. At this temperature, a solution of methyl2-[bis(tert-butoxycarbonyl)]amino-prop-2-enoate (100 g, 332 mmol;prepared in accordance with K. El Abdioui et al., Bull. Soc. Chim. Belg.1997, 106, 425) in tetrahydrofuran (70 ml) is added, the mixture isstirred for further 4 h at −5° C. and then warmed to RT.

Step 2

The reaction mixture obtained in step 1 is admixed with 23% sodiumhydroxide solution (290 g, 1.6 mol) and heated under reflux for 7 h.Tetrahydrofuran is distilled off, the reaction solution is cooled to RTand extracted with methyl tert-butyl ether (400 ml). The aqueoUs phaseis diluted with isopropanol (260 ml) and admixed with 2N sulfuric aciduntil pH 4 is reached. The precipitated solid is filtered off withsuction and dried to give2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid(82 g, 69%) as a cream-colored solid.

C₁₈H₂₂N₄O₄, M=358.40 g/mol; MS (ESI): m/z=359 ((M+1)⁺, 100%); ¹H-NMR(400 MHz, DMSO-d₆): δ=12.60 (bs, 1 H), 8.36 (d, J=4.8 Hz, 2 H),7.42-7.36 (m, 2 H), 7.30-7.21 (m, 3 H), 7.05 (t, J=8.3 Hz, 1 H), 6.76(t, J=4.8 Hz, 1 H), 4.48-4.30 (m, 2 H), 4.12-4.01 (m, 1 H), 1.31 (s, 9H) ppm; melting point: 165° C. (decomposition).

EXAMPLE 2 Preparation of (S)-1-phenylethyl-ammonium(S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoate

Step 1

A suspension of2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acidprepared as in Example 1 (120 g, 335 mmol) in n-butyl acetate (1000 ml)is admixed at 50° C. with (S)-1-phenylethyl-amine (38.5 g, 318 mmol;99.7% chemical purity, 99.3% ee (enantiomeric excess); BASF), themixture stirred for further 2 h at this temperature and then cooled toRT. The precipitated solid is filtered off with suction and dried togive a cream-colored crystalline crude product (83.9 g) which is Useddirectly in step 2.

Step 2

The crude product (83.9 g) obtained in step 1 is heated under reflux for2 h in ethyl acetate (590 ml) and then cooled to 5° C. The solid isfiltered off with suction and dried to give (S)-1-phenylethyl-ammonium(S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoate(72.1 g, 45%, 99.5% de (diastereomeric excess)) as a colorless solid.

C₂₆H₃₃N₅O₄, M=479.58 g/mol; ¹H-NMR (400 MHz, methanol-d₄): δ=8.31 (d,J=5.0 Hz, 2 H), 7.51-7.41 (m, 7 H), 7.39-7.30 (m, 3 H), 6.69 (m, 1 H),4.55 (m, 1 H), 4.43 (m, 1 H), 4.40 (q, J=7.0 Hz, 1 H), 4.18 (m, 1 H),1.60 (d, J=7.0 Hz, 3 H), 1.31 (s, 9 H) ppm; melting point: 174° C.

EXAMPLE 3 Preparation of(S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoicacid

A sUspension of (S)-1-phenylethyl-ammonium(S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoate(37.2 g, 77.5 mmol, 99.5% de) in aqueoUs isopropanol (50% strength, 90ml) is admixed with 1N sulfuric acid (97 ml, 48.5 mmol) and stirred for1 h at RT. The solid is filtered off with suction and dried to give(S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoicacid (26.5 g, 95%, >99.9% ee) as a colorless solid.

C₁₈H₂₂N₄O₄, M=358.40 g/mol; MS (ESI): m/z=359 ((M+1)⁺, 100%); ¹H-NMR(400 MHz, DMSO-d₆): δ=12.60 (bs, 1 H), 8.36 (d, J=4.8 Hz, 2 H),7.42-7.36 (m, 2H), 7.30-7.21 (m, 3 H), 7.05 (t, J=8.3 Hz, 1 H), 6.76 (t,J=4.8 Hz, 1 H), 4.48-4.30 (m, 2 H), 4.12-4.01 (m, 1 H), 1.31 (s, 9 H)ppm; HPLC (column: Chiralpak AD-H, 250×4.6 mm, n-heptane+0.1%TFA:ethanol+0.1% TFA 95:5, 1 ml/min, 254 nm): retention time [min]=19.1(S), 21.4 (R).

EXAMPLE 4 Preparation of(S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoicacid amide

A suspension of(S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoicacid (11.9 g, 33.2 mmol, >99.9% ee) in acetonitrile (36 ml) is admixedat −15° C. with a solution of 1,1′-carbonyldiimidazole (8.36 g, 51.6mmol) in acetonitrile (125 ml), and the reaction mixture is stirred for2 h at this temperature. Ammonia (4.0 g, 222 mmol) is then introduced,and the mixture is stirred for further 1 h and then adjUsted to pH 4.5Using 2N sulfuric acid. Acetonitrile is distilled off, and theprecipitated solid is filtered off with suction and dried to give(S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoicacid amide (11.3 g, 95%, >99.9% ee) as a colorless solid.

C₁₈H₂₃N₆O₃, M=357.42 g/mol; MS (ESI): m/z=358 ((M+1)⁺, 100%); ¹H-NMR(400 MHz, DMSO-d₆): δ=8.41 (d, J=5.0 Hz, 2 H), 7.50-7.43 (m, 2 H),7.35-7.28 (m, 4 H), 7.17 (s, 1 H), 6.79 (t, J=5.0 Hz, 1 H), 6.68 (d,J=9.0 Hz, 1H), 4.36 (m, 1 H), 4.23 (m, 1 H), 4.08 (m, 1 H), 1.31 (s, 9H) ppm; HPLC (column: Chiralpak AD-H, 250×4.6 mm, n-heptane:ethanol80:20, 1 ml/min, 254 nm): retention time [min]=7.2 (S), 9.2 (R); meltingpoint: 157° C. (decomposition).

EXAMPLE 5 Preparation of(S)-2-amino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide

(S)-2-tert-Butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoicacid amide (48.5 g, 136 mmol, >99.9% ee) is introduced at 40° C. inportions into hydrochloric acid (16% strength, 80 ml), and the resultingsolution is stirred for 1 h at this temperature. After cooling to 5° C.,the pH is adjUsted to 10 by adding concentrated potassium hydroxidesolution. The precipitated solid is filtered off with suction and driedto give (S)-2-amino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide(35.3 g, 80% yield, 79% content, 99.8% ee) as a colorless solid, whichcan be further reacted or else crystallized again from aqueoUs solution,as desired.

C₁₃H₁₆N₆O, M=257.29 g/mol; MS (ESI): m/z=258 ((M+1)⁺, 100%); ¹H-NMR (400MHz, DMSO-d₆): δ=8.37 (d, J=4.8 Hz, 2 H), 7.50-7.39 (m, 5 H), 7.28 (t,J=7.3 Hz, 1 H), 7.06 (bs, 1 H), 6.73 (t, J=4.8 Hz, 1 H), 4.30 (dd, J=9.6and 14.4 Hz, 1 H), 3.92 (dd, J=5.3 and 14.3 Hz, 1 H), 3.43 (dd, J=5.2and 9.5 Hz, 1 H), 1.83 (bs, 2 H) ppm; HPLC (column: Chiralpak AS,250×4.6 mm, ethanol+0.1% diethylamine:methanol+0.1% diethylamine 50:50,1 ml/min, 231 nm): retention time [min]=4.5 (S), 6.8 (R); melting point:139° C.

EXAMPLE 62-tert-Butoxycarbonylamino-3-(phenyl-pyridin-2-ylamino)-propanoic acid

Step 1

A suspension of 2-anilino-pyridine (3.40 g, 20.0 mmol) and cesiumcarbonate (3.26 g, 10.0 mmol) in diisopropyl ether (12 ml) is admixedwith methyl 2-[bis(tert-butoxycarbonyl)]amino-prop-2-enoate (6.03 g,20.0 mmol) and heated under reflux for 23 h. The sUspension is filteredhot, and the solution obtained is evaporated under reduced pressure.

Step 2

The crude product obtained in step 1 is dissolved in tetrahydrofuran (30ml), admixed with 32% strength sodium hydroxide solution (10 ml) andheated under reflux for 4 h. The resulting suspension is filtered, andthe solution obtained is admixed with water. Tetrahydrofuran isdistilled off and the aqueous solution is extracted with methyltert-butyl ether. The aqueoUs phase is diluted with isopropanol (30 ml)and admixed with 2N sulfuric acid until pH 4 is reached. Theprecipitated solid is filtered off with suction and dried to give2-tert-butoxycarbonylamino-3-(phenyl-pyridin-2-ylamino)-propanoic acid(2.25 g, 32%) as a cream-colored solid.

C₁₉H₂₃N₃O₄, M=357.41 g/mol; MS (ESI): m/z=358 ((M+1)⁺, 100%); ¹H-NMR(400 MHz, methanol-d₄): δ=8.17 (m, 1H), 7.51-7.32 (m, 6 H), 6.73 (t,J=6.1 Hz, 1 H), 6.39 (m, 1 H), 4.41 (m, 2 H), 4.28 (m, 1 H), 1.39 (s,9H) ppm; melting point 140° C. (decomposition).

EXAMPLE 7 Methyl2-[bis(tert-butoxycarbonyl)]amino-3-(phenyl-pyridin-2-ylamino)-propanoate

An aliquot of the reaction mixture obtained in step 1 of example 6 isdiluted with diisopropyl ether and admixed with 2N sulfuric acid untilpH 5 is reached. The precipitated solid is filtered off with suction anddried to give methyl2-[bis(tert-butoxycarbonyl)]amino-3-(phenyl-pyridin-2-ylamino)-propanoateas a yellow solid.

C₂₅H₃₃N₃O₆, M=471.56 g/mol; MS (ESI): m/z=472 ((M+1)⁺, 100%); ¹H-NMR(400 MHz, DMSO-d₆): δ=8.17 (d, J=3.9 Hz, 1 H), 7.45 (m, 2 H), 7.38 (m, 1H), 7.30-7.20 (m, 3 H), 6.67 (t, J=6.2 Hz, 1 H), 6.26 (d, J=8.6 Hz, 1H), 5.71 (dd, J=4.3 and 10.1 Hz, 1 H), 4.67 (dd, J=4.3 and 14.1 Hz, 1H), 4.17 (dd, J=10.3 and 14.1 Hz, 1 H), 3.67 (s, 3 H), 1.20 (s, 18 H)ppm; melting point 103° C.

EXAMPLE 8 (S)-1-Phenylethyl-ammonium(S)-2-tert-butoxycarbonylamino-3-(phenyl-pyridin-2-ylamino)-propanoate

Step 1

A suspension of2-tert-butoxycarbonylamino-3-(phenyl-pyridin-2-ylamino)-propanoic acid(6.80 g, 19.0 mmol) in diisopropyl ether (50 ml) is admixed at 60° C.with a solution of (S)-1-phenylethyl-amine (2.20 g, 18.2 mmol) indiisopropyl ether (10 ml). The mixture is stirred at this temperaturefor a further hour and then cooled to RT. The precipitated solid isfiltered off with suction and dried to give a cream-colored crystallinecrude product (3.50 g), which is directly used in step 2.

Step 2

The crude product (3.50 g) obtained in step 1 is heated under reflux for1 h in diisopropyl ether (70 ml) and then cooled to RT. The solid isfiltered off with suction and dried to give (S)-1-phenylethyl-ammonium(S)-2-tert-butoxycarbonylamino-3-(phenyl-pyridin-2-ylamino)-propanoate(2.40 g, 28%, 99.5% de) as a colorless solid.

C₂₇H₃₄N₄O₄, M=478.6 g/mol; ¹H-NMR (400 MHz, methanol-d₄): δ=8.10 (m, 1H), 7.50-7.25 (m, 11 H), 6.65 (m, 1 H), 6.38 (m, 1 H), 4.61 (m, 1 H),4.40 (q, J=7.1 Hz, 1 H), 4.30 (m, 1 H), 4.05 (m, 1 H), 1.61 (d, J=7.1Hz, 3 H), 1.30 (s, 9 H) ppm; melting point 131° C. to 136° C.

EXAMPLE 9(S)-2-tert-Butoxycarbonylamino-3-(phenyl-pyridin-2-ylamino)-propanoicacid

A suspension of (S)-1-phenylethyl-ammonium(S)-2-tert-butoxycarbonylamino-3-(phenyl-pyridin-2-ylamino)-propanoate(2.25 g, 4.69 mmol, 99.5% de) in aqueous isopropanol (50% strength, 6ml) is admixed with 1N sulfuric acid (6 ml, 5.85 mmol) and stirred for 2h at RT. The solid is filtered off with suction and dried to give(S)-2-tert-butoxycarbonylamino-3-(phenyl-pyridin-2-ylamino)-propanoicacid (1.35 g, 81%, >99.9% ee) as a colorless solid.

C₁₉H₂₃N₃O₄, M=357.41 g/mol; MS (ESI): m/z=358 ((M+1)⁺, 100%); ¹H-NMR(400 MHz, methanol-d₄): δ=8.17 (m, 1H), 7.51-7.32 (m, 6 H), 6.73 (t,J=6.1 Hz, 1 H), 6.39 (m, 1 H), 4.41 (m, 2 H), 4.28 (m, 1 H), 1.39 (s, 9H) ppm; HPLC (column: Chiralcel OD-H, 250×4.6 mm, n-heptane+0.1%TFA:ethanol+0.1% TFA 97:3, 1.2 ml/min, 240 nm): retention time [min]=9.7(S), 11.5 (R); melting point 144° C. (decomposition).

What is claimed is:
 1. A process for obtaining a compound of formula IIIor a salt thereof:

wherein R1 is a hydrogen atom, F, Cl, I, Br, (C₁-C₄)-alkyl or —CN; andR2 is a heteroaryl residue selected from the series consisting ofpyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole,thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides,triazolones, oxadiazolone, isoxazolone, oxadiazolidinedione, triazole,3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine,pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine,quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline andβ-carboline, wherein the heteroaryl residue is unsubstituted or issubstituted once, twice or three times, independently of each other, bysubstituents selected from the series consisting of (C₁-C₅)-alkyl,(C₁-C₅)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy,hydroxy-(C₁-C₄)-alkyl-, methylenedioxy, ethylenedioxy, formyl, acetyl,cyano, hydroxycarbonyl-, aminocarbonyl- and (C₁-C₄)-alkoxycarbonyl-, oran aryl residue selected from the series consisting of phenyl, naphthyl,1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, anthryl and fluorenyl, wherein the aryl residue isunsubstituted or is substituted once, twice or three times,independently of each other, by substituents selected from the seriesconsisting of (C₁-C₅)-alkyl, (C₁-C₅)-alkoxy, halogen, nitro, amino,trifluoromethyl, hydroxy, hydroxy-(C₁-C₄)-alkyl-, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl-, aminocarbonyl-and (C₁-C₄)-alkoxycarbonyl-; R5 is —NH₂, —N(H)-R6 or —N(R6)₂, wherein R6is (C₁-C₄)-alkyl or aryl, wherein the aryl residue is selected from theseries consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl,biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl andfluorenyl; said process comprising a) mixing a compound of formula II:

wherein R1 and R2 are as defined above, and R3 is a hydrogen atom, or(C₁-C₄)-alkyl, or an aryl residue selected from the series consisting ofphenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl,3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl, wherein the arylresidue is unsubstituted or is substituted, independently of each other,once, twice or three times by substituents selected from the seriesconsisting of —NO₂, —O—(C₁-C₄)-alkyl, F, CI and Br, or —O—C(CH₃)₃, or—O—CH(R7)-aryl, wherein the aryl residue is selected from the seriesconsisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl,2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl and fluorenyl and isunsubstituted or is substituted, independently of each other, once,twice or three times by substituents selected from the series consistingof —NO₂,—O—CH₃, F, Cl and Br, and wherein R7 is a hydrogen atom or(C₁-C₄)-alkyl; in an organic solvent or a mixture of organic solventswith an enantiomerically pure auxiliary; b) separating the salt composedof enantiomerically pure auxiliary and compound of formula I:

by fractional crystallization; c) isolating the compound of formula Ifrom the salt composed of enantiomerically pure auxiliary and compoundof formula I; d) converting the resulting compound of formula I withammonia or an amine of the formula H₂N-R6 or HN(R6)₂, wherein R6 is(C₁-C₄)-alkyl or aryl, wherein the aryl residue is selected from theseries consisting of phenyl, naphthyl, 1-naphthyl, 2-naphthyl,biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, anthryl andfluorenyl, into a compound of formula IV:

or a salt thereof; and e) converting the resulting compound of formulaIV or salt thereof into the compound of formula III or a salt thereof.2. The process as claimed in claim 1, wherein a compound of formula IIIor a salt thereof is obtained, wherein R1 is a hydrogen atom, F, CI, Ior Br; R2 is phenyl, pyridinyl, pyrimidinyl or thiazolyl, whereinphenyl, pyridinyl, pyrimidinyl and thiazolyl are unsubstituted orsubstituted by fluorine or chlorine; R5 is —NH₂, —N(H)-R6 or —N(R6)₂,wherein R6 is (C₁-C₄)-alkyl or aryl, wherein the aryl residue isselected from the series consisting of phenyl, naphthyl, 1-naphthyl,2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,anthryl and fluorenyl.
 3. A compound of formula III, selected from theseries consisting of(S)-2-amino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide (formulaIIIa), or a salt thereof, and(R)-2-amino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide (formulaIIIb), or a salt thereof: